Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases

Kostoulas, Georgios; Lang, Angela; Nagase, Hideaki; Baici, Antonio

doi:10.1016/s0014-5793(99)00897-2

Cited by 153 publications

(96 citation statements)

References 32 publications

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“…We are currently examining our antisense cathepsin B clones to see if their decreased invasiveness relates to reduction in cathepsin B-mediated activation of plasminogen activators, the proteolytic cascade involved in the degradation of extracellular matrix components. A recent study suggested that besides directly participating in tissue destruction, cathepsin B enhances the activity of matrix metalloproteinases by degrading their inhibitors tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 in human articular chondrocytes (Kostoulas et al, 1999). However, whether similar mechanisms are operative in the glioblastoma cells we used in our study is not known.…”

Section: Discussionmentioning

confidence: 85%

Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells

et al. 2001

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Increases in abundance of cathepsin B transcript and protein correlate with increases in tumor grade and alterations in subcellular localization and activity of cathepsin B. The enzyme is able to degrade the components of the extracellular matrix (ECM) and activate other proteases capable of degrading ECM. To investigate the role played by this protease in the invasion of brain tumor cells, we transfected SNB19 human glioblastoma cells with a plasmid containing cathepsin B cDNA in antisense orientation. Control cells were transfected with vector alone. Clones expressing antisense cathepsin B cDNA exhibited signi®cant reductions in cathepsin B mRNA, enzyme activity and protein compared to controls. Matrigel Invasion assay showed that the antisense-transfected cells had a markedly diminished invasiveness compared with controls. When tumor spheroids containing antisense transfected SNB19 cells expressing reduced cathepsin B were co-cultured with fetal rat brain aggregates, invasion of fetal rat brain aggregates was signi®cantly reduced. Green Fluorescent Protein (GFP) expressing parental cells and antisense transfectants were generated for detection in mouse brain tissue without any postchemical treatment. Intracerebral injection of SNB19 stable antisense transfectants resulted in reduced tumor formation in nude mice. These results strongly support a role for cathepsin B in the invasiveness of human glioblastoma cells and suggest cathepsin B antisense may prove useful in cancer therapy. Oncogene (2001) 20, 3665 ± 3673.

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Section: Discussionmentioning

confidence: 85%

Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells

et al. 2001

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“…Finally, cathepsin B and metalloproteases may form a proteolytic cascade. For instance, it has been shown that cathepsin B inactivates tissue inhibitors of membrane metalloprotease, thus leading to increased metalloprotease activity (56). Furthermore, there is precedence for growth factor activation as a result of cleavage by cathepsin B (57), and cathepsin B has been shown to cause peptide cleavage at the same sites as membrane metalloproteases (58).…”

Section: Discussionmentioning

confidence: 99%

IL-8-Mediated Cell Migration in Endothelial Cells Depends on Cathepsin B Activity and Transactivation of the Epidermal Growth Factor Receptor

Schraufstätter

Trieu

Zhao

et al. 2003

The Journal of Immunology

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Microvascular endothelial cells (HMECs) express both the CXCR1 and the CXCR2, but cell migration is almost entirely mediated by the CXCR2. Similarly, NIH 3T3 cells transfected with the CXCR2 migrated toward IL-8, whereas CXCR1-transfected cells failed to do so. This situation differs from that seen in leukocytes, where chemotaxis is primarily a function of the CXCR1. To define signal transduction pathways that explain this difference in behavior, various inhibitors were used to block cell migration. Apart from inhibitors of phosphatidylinositol 3-kinase, which blocked migration in all cases, inhibition of the epidermal growth factor (EGF) receptor blocked IL-8-mediated cell migration in HMECs and in CXCR2-transfected NIH 3T3 cells, but not in RBL2H3 cells, which do not express an EGFR. Blocking Abs against the EGFR or against heparin-binding EGF-like growth factor similarly blocked IL-8-mediated cell migration and in vitro tubulogenesis in HMECs. Furthermore, inhibition of the EGFR also attenuated focus formation in NIH 3T3 expressing the CXCR2. Immunoprecipitations of the EGFR in HMECs and in NIH 3T3 cells expressing the CXCR2 confirmed that the EGFR was phosphorylated following stimulation with IL-8. However, in contrast to previous reports, e.g., for the thrombin receptor, inhibition of matrix metalloproteases blocked IL-8-mediated cell migration only partially, whereas it was ablated by inhibition of cathepsin B. These results indicate that IL-8-induced transactivation of the EGFR is mediated by the CXCR2 and involves cathepsin B, and that this pathway is important for the migratory and tumorigenic effects of IL-8.

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“…Likewise, strong immunostaining of cathepsin B was observed in rat brain microvascular endothelial cells as they formed capillary tubes in vitro (Keppler et al, 1996). Since cathepsin B was shown to be an inhibitor of TIMPs (Kostoulas et al, 1999) and TIMPs are inhibitors of angiogenesis, cathepsin B could also stimulate angiogenesis, which has an important role in tumor spread. It has been reported in the host results in the enhanced adhesion of uPAR-bearing endothelial cells to the ECM protein vitronectin due to the loss of PAI-1, which adversely affects cell motility and resultant neovascularization (Gutierrez et al, 2000).…”

Section: Cathepsin B and Upar Sirna Suppresses Intracranial Tumor Growthmentioning

confidence: 97%

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

et al. 2004

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RNA interference (RNAi) provides a powerful method for gene silencing in eukaryotic cells, including proliferating mammalian cells. Here, we determined whether RNAi could be utilized to inhibit the expression of proteases implicated in the extracellular matrix degradation, which is characteristic of tumor progression. We have previously shown that antisense stable clones of uPAR and cathepsin B were less invasive and did not form tumors when injected intracranially ex vivo. Since antisense-mediated gene silencing does not completely inhibit the translation of target mRNA and high molar concentrations of antisense molecules are required to achieve gene silencing, we used the RNAi approach to silence uPAR and cathepsin B in this study. We found that the expression of doublestranded RNA leads to the efficient and specific inhibition of endogenous uPAR and cathepsin B protein expression in glioma cell lines as determined by Western blotting. We also found the RNAi of uPAR and cathepsin B reduces glioma cell invasion and angiogenesis in in vitro and in vivo models. Intratumoral injections of plasmid vectors expressing hpRNA for uPAR and cathepsin B resulted in the regression of pre-established intracranial tumors. Further, RNAi for uPAR and cathepsin B inhibited cell proliferation and reduced the levels of pERK and pFAK compared to controls. Taken together, our findings indicate for the first time that RNAi operates in human glioma cells with potential application for cancer gene therapy.

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Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases

Cited by 153 publications

References 32 publications

Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells

Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells

IL-8-Mediated Cell Migration in Endothelial Cells Depends on Cathepsin B Activity and Transactivation of the Epidermal Growth Factor Receptor

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

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